Phenocopying ATM loss via modulation of cellular metabolism to overcome resistance to the ATR inhibitor

我们的目标是：(i)通过研究ATM缺乏对细胞代谢的影响来表征ATM在产生atr抑制剂耐药性中的作用；（ii）研究我们是否可以通过靶向细胞代谢来重建ATM缺陷细胞的代谢谱，以及这是否会使癌细胞对AZ6738敏感，模拟ATM的损失。了解ATM如何有助于产生对AZ6738（一种目前处于临床试验中的药物）的耐药性，我们的建议与制药行业明确相关，因此属于BBSRC的职权范围。目的1：利用示踪化合物和未发表的AZ初步数据，我们将研究导致ATM缺陷细胞代谢谱的机制。Aim2：抑制剂已经可用于大多数代谢途径，因此我们将利用这个未被开发的工具箱来反映Aim1中鉴定的ATM缺陷代谢表型，并测试这是否会使ATM精通细胞对AZ6738敏感。目的：在共济失调-毛细血管扩张患者的小脑皮质（携带ATM基因突变）中，一组线粒体基因被解除调控。与GS （UCL -第二主管）合作，我们将使用公开可用的数据集（即CCLE）识别具有相似线粒体表型的细胞，并将测试具有不同线粒体表型的细胞对AZ6738的敏感性。预期结果：了解细胞代谢的变化如何导致耐药性

Our objectives are (i) to characterise the role of ATM in generating resistance toATR inhibitors by investigating the effect of ATM deficiency on cellular metabolism; (ii) to investigatewhether we can recreate the metabolic profile of ATM-deficient cells via targeting cellular metabolism and ifthis would sensitize cancer cells to AZ6738, mimicking ATM loss. Understand how ATM contributes togenerate resistance to AZ6738, a drug currently in clinical trials, our proposal is of clear relevance for thepharmaceutical industry and thus in the remit of BBSRC.Aim1: Using tracer compounds and unpublished preliminary data form AZ, we will investigate themechanisms responsible for the metabolic profile of ATM deficient cells.Aim2: inhibitors are already available for the majority of metabolic pathways, thus we will take advantage ofthis underexploited toolbox to mirror the ATM-deficient metabolic phenotype identified in Aim1 and test ifthis will sensitise ATM proficient cells to AZ6738.Aim3: in the cerebellar cortex of Ataxia-telangiectasia patients (carrying mutations in the ATM gene) a set ofmitochondrial genes is deregulated5. In collaboration with GS (UCL - second supervisor) we will identifycells with a similar mitochondrial phenotype using publicly available dataset (i.e. CCLE) and will test thesensitivity to AZ6738 of cells with different mitochondria phenotypes.Expected outcome: understand how changes in cellular metabolism may lead to drug resistance